Based on favorable results from phase 2 studies, two phase 3 trials were initiated to compare the neurosteroid progesterone to placebo in the treatment of traumatic brain injury (TBI).

Neither study showed improvement over placebo, and the PROTECT III trial was halted early because of futility. Side-effect profiles were similar between progesterone and placebo groups in the studies.

Researchers suggest that study protocols may have to be changed dramatically in the search for an effective treatment for TBI.

Précis

Based on favorable results from phase 2 studies, two phase 3 trials were initiated to compare the neurosteroid progesterone to placebo in the treatment of traumatic brain injury (TBI).

Neither study showed improvement over placebo, and the PROTECT III trial was halted early because of futility. Side-effect profiles were similar between progesterone and placebo groups in the studies.

Researchers suggest that study protocols may have to be changed dramatically in the search for an effective treatment for TBI.

The attempt to identify a single effective treatment to improve outcomes for those who incur a traumatic brain injury (TBI) continues to frustrate researchers. Two recently published phase 3 trials failed to replicate results of earlier phase 2 studies that had shown a favorable response to the neurosteroid progesterone.

The annual cost of TBI nationally has been estimated at around $76.5 billion, and survivors of severe TBI usually need 5 to 10 years of intensive therapy and often must live with significant disability. No pharmacologic treatment has been shown to improve post-TBI outcomes. However, animal studies and two single-center clinical trials have fueled interest in progesterone for this indication, with the latter studies showing decreased mortality and improved functional outcomes compared with placebo.

Two phase 3 trials were initiated based on the phase 2 results. The Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment (PROTECT III) trial examined the efficacy of early administration of progesterone for treatment of TBI ranging from severe to moderate. The Study of a Neuroprotective Agent, Progesterone, in Severe Traumatic Brain Injury (SYNAPSE) trial examined progesterone in a sample of only patients with severe TBI.

Study details

The PROTECT III trial, conducted at 49 trauma centers, enrolled adults with severe, moderate-to-severe, or moderate TBI who had a score of 4 to 12 on the Glasgow Coma Scale (GCS), which ranges from 3 to 15, with lower scores corresponding to a lower level of consciousness. Among the exclusion criteria were a determination that the injury was not survivable or that the patient had hypotension, spinal cord injury, active myocardial infarction, ischemic stroke, or several other major complicating comorbidities.

Progesterone or placebo was initiated within 4 hours after injury, with a 1-hour leading dose, 71 hours of maintenance infusion, and a 24-hour infusion taper. The leading dose was 14.3 mL, followed by 10 mL/hour for 71 hours and then a taper by 2.5 mL/hour every 8 hours. The primary outcome was functional recovery as measured by the Extended Glasgow Outcome Scale (GOS-E) at 6 months after randomization, with the criterion for functional recovery based on the severity of each patient’s initial injury.

The SYNAPSE trial enrolled patients with severe TBI only, with the requirement of a GCS score of 8 or lower. Exclusion criteria were similar to those used in the PROTECT III trial. Treatment was initiated within 8 hours after injury.

Dosing in the first hour was 0.71 mg/kg of body weight, followed by 0.50 mg/kg for 119 hours. The primary outcome was the Glasgow Outcome Scale (GOS) score 6 months after the initial injury.

Results

A total of 882 patients were randomized in the PROTECT III trial, with 53.5% having a moderate-to-severe brain injury. After the second interim analysis took place, the trial was stopped because of futility; 51% of progesterone patients had achieved favorable outcomes, compared with 55.5% of placebo patients. The overall 6-month mortality rate was 17.2%, with no significant difference between the two patient groups. Progesterone had an acceptable safety profile in the study, although phlebitis and thrombophlebitis were more common in the progesterone group than in the placebo group.

A total of 1,195 patients were randomized in the SYNAPSE trial. There was no significant difference between treatment groups in the primary outcome of GOS score at 6 months. Favorable outcomes were achieved in 50.4% of progesterone patients and 50.5% of placebo patients. There were no significant differences in adverse events between the two patient groups.

Implications

The authors of the PROTECT III trial wrote, “The PROTECT III trial joins a growing list of negative or inconclusive trials in the arduous search for a treatment for TBI.” They cited several possible explanations that have been offered for this, including limited preclinical development work, delayed initiation of treatment, and heterogeneity of the brain injuries incurred by patients.

The authors of the SYNAPSE trial wrote, “TBI is a complex, heterogeneous disorder, in which the primary injury initiates a variety of secondary injury cascades. These cascades involve processes that may not be responsive to monotherapy.…”

Researchers in these two trials suggest that the search for an effective treatment for TBI may require new research paradigms, including adaptive clinical trial designs in early phases and rigorous preclinical trials in animals that better simulate human trials.

In an accompanying editorial to the two progesterone trials, Lee H. Schwamm, M.D., of the Department of Neurology, TeleStroke and Acute Stroke Services at Massachusetts General Hospital, wrote that the failed phase 3 results reflect deficiencies in the studies that preceded these trials. He stated that although the benefit seen in the phase 2 trials of progesterone was modest, investigators and funders were convinced enough to pursue phase 3 studies.

Schwamm suggested “a radical change in the culture of investigation and its funding,” including more rigorous reporting of preclinical data, as well as coordinated phase 2 trials that use standardized outcomes.

For the PROTECT III trial, lead author David W. Wright, M.D., reported receiving royalties from a patent related to progesterone for the treatment of TBI.

Eighteen patients with depression that had not responded to at least one prior antidepressant trial received administrations of intranasal ketamine 50 mg or placebo in two sessions at least 7 days apart.

The percentage of responders with intranasal ketamine was lower than what has been observed in some prior studies of intravenous ketamine.

Précis

Eighteen patients with depression that had not responded to at least one prior antidepressant trial received administrations of intranasal ketamine 50 mg or placebo in two sessions at least 7 days apart.

The percentage of responders with intranasal ketamine was lower than what has been observed in some prior studies of intravenous ketamine.

A new randomized, double-blind crossover study has found that a single 50-mg dose of intranasal ketamine was associated with rapid antidepressant response in patients with treatment-resistant depression, with a significant effect seen 40 minutes after administration.

The search for novel strategies for treatment-resistant depression has recently focused on the glutamate system. Several studies have found rapid antidepressant effects from intravenous ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, but there have been concerns about limitations of this route of administration because of factors such as its lack of availability in most clinical practices and patient resistance.

In order to examine whether an alternative route of ketamine administration might prove viable, a proof-of-concept trial examined the short-term effects of a 50-mg intranasal dose of ketamine in patients with depression who had not responded to at least one prior antidepressant trial.

Study details

Adults ages 21 to 65 with a primary diagnosis of chronic or recurrent depression were eligible to participate. They were required to have a baseline score of at least 30 on the Inventory of Depressive Symptoms-Clinician Rated. Exclusion criteria included but were not limited to a primary Axis I disorder other than depression, a high risk of suicide, or a psychotic or bipolar disorder.

In the crossover design, each participant received a dose of ketamine 50 mg or placebo at least 7 days apart. Ketamine was provided in five applications of 10 mg each over a 20-minute period, and patients were observed on the research unit for at least 4 hours after administration.

The primary outcome was change in depression severity 24 hours after administration, using the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary measures included the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR), the Hamilton Anxiety Rating Scale (HAM-A), and the percentage of individuals in each group who met criteria for response, defined as a decrease of at least 50% in the MADRS score from baseline.

Results

Eighteen patients completed both treatment periods, receiving either ketamine followed by placebo or the reverse. These individuals had failed an average of 4.1 ± 3.9 prior adequate antidepressant trials and had been experiencing depression symptoms for an average of 27 years.

Study authors found that depressive symptoms 24 hours after treatment administration were significantly improved with intranasal ketamine compared with placebo (p<.001). At this 24-hour stage, 8 of 18 ketamine patients met response criteria, compared with only 1 of 18 placebo patients. Response to ketamine also separated from response to placebo at 40 minutes, 240 minutes, and 48 hours, but not at 72 hours or 7 days.

The authors found that intranasal ketamine was associated with small increases on measures of psychosis and dissociation, as well as small increases in systolic blood pressure. The most commonly reported treatment-emergent adverse events among ketamine patients 4 hours after administration were feeling strange, having poor memory, and feeling weakness or fatigue.

Implications

The authors stated that this study offers the first randomized controlled evidence that intranasal ketamine is safe and effective for rapid reduction of depressive symptoms in patients with treatment-resistant depression. The percentage of treatment responders, however, was lower for intranasal ketamine than what was observed in previous studies of intravenous ketamine; this may have been a result of lower blood levels of ketamine with intranasal administration.

Because the study allowed patients to continue to use antidepressant medications during the study period, this made it impossible for the researchers to distinguish between effects of ketamine in isolation and possible benefits of ketamine with antidepressants. The study’s relatively small sample size also was cited as one of its limitations.

The study’s authors wrote, “Much more research is required to determine the optimal dose, duration, frequency, and route of administration of ketamine for depression.”

Study co-author Dennis S. Charney is named on a use patent on ketamine for the treatment of depression. Several other co-authors report research support or consulting arrangements with pharmaceutical companies.

Although a recent study did not find that use of recombinant human erythropoietin, a glycoprotein hormone, improved the primary outcome for persons with treatment-resistant depression, authors said enough promising results from the treatment were observed to warrant further investigation.

In the search for treatments to help the 30% to 40% of patients who do not respond fully to current antidepressant treatment strategies, researchers have explored evidence that restoration of synaptic plasticity might serve as an important factor in facilitating improvement. Erythropoietin’s main function is to control red blood cell production but it also is produced in the brain and has a significant role in neuroprotection. In previous research, a single dose of erythropoietin was shown to improve neurocognitive function in persons with depression.

précis

• Patients with treatment-resistant depression were randomized to receive weekly infusions of either erythropoietin (40,000 IU) or saline over 8 weeks, along with continuing on their antidepressant medication.

• There was no effect of erythropoietin over saline at week 9 or 14 on the primary outcome measure of change in the Hamilton Depression Rating Scale (HDRS-17), but erythropoietin patients did see improvement on other mood and memory measures.

• Researchers believe these results warrant larger-scale studies to examine further the potential of this hormone in addressing treatment-resistant depression.

Although a recent study did not find that use of recombinant human erythropoietin, a glycoprotein hormone, improved the primary outcome for persons with treatment-resistant depression, authors said enough promising results from the treatment were observed to warrant further investigation.

In the search for treatments to help the 30% to 40% of patients who do not respond fully to current antidepressant treatment strategies, researchers have explored evidence that restoration of synaptic plasticity might serve as an important factor in facilitating improvement. Erythropoietin’s main function is to control red blood cell production but it also is produced in the brain and has a significant role in neuroprotection. In previous research, a single dose of erythropoietin was shown to improve neurocognitive function in persons with depression.

Authors of this latest research conducted an exploratory study to determine whether the beneficial effects seen in a single dose administration could be observed for mood and memory with multiple doses.

Study details

Patients eligible for the study were adults ages 18 to 65 with major depression of moderate severity and treatment resistance based on not achieving remission after at least two adequate antidepressant treatments from different classes in previous and/or current episodes.

Exclusion criteria included but were not limited to significant medical illness, bipolar disorder, schizophrenia, and alcohol or drug misuse.

Patients were randomized to receive weekly infusions of either erythropoietin (40,000 IU) or saline over 8 weeks, and continued on their previous antidepressant medication regimen. Researchers measured patients’ depressive symptoms, psychosocial functioning, and quality of life in weeks 1, 5, 9, and 14.

The primary outcome in the study was change in the Hamilton Depression Rating Scale (HDRS-17) from baseline to week 9. Remission rate, based on an HDRS score < 8, was the secondary outcome measure evaluated.

Results

Data were analyzed for 39 patients (18 receiving erythropoietin and 21 receiving saline), and 4 erythropoietin patients and 1 saline patient did not complete treatment. Three of the erythropoietin patients discontinued treatment because of increased thrombocytes, while one was hospitalized because of acute suicide risk.

There was no effect of erythropoietin over saline at week 9 or 14 on the primary outcome measure of change in the HDRS-17. However, erythropoietin patients did show improvement over saline patients on several other measures, such as the Beck Depression Inventory-21 (BDI-21), enhanced total recall across five learning trials measuring verbal memory, and recognition memory scores.

Moreover, when a group of 8 patients who experienced unforeseen mood improvement just prior to the start of the trial were excluded and an analysis of the remaining subgroup was performed, the latter group saw a beneficial effect from erythropoietin on the primary outcome (p = 0.02), an effect that was sustained at week 14.

The authors did not find any serious adverse events over the course of the study.

Implications

While the authors acknowledged that “the study must be declared formally negative” because of the lack of efficacy on the primary outcome measure, further analysis did offer an indication of some antidepressant efficacy for erythropoietin. They added that this should encourage additional trials on a larger scale to explore the hormone’s potential in depression treatment.

Improvements in memory substantially exceeded the researchers’ prior estimation of a clinically relevant change based on an earlier study. Because of memory’s role in cognitive function, “It is also tempting to speculate that [erythropoietin] could be implemented to aid speed of recovery and effectiveness of cognitive behavioral therapy for treatment-resistant depression,” the authors stated.

Several limitations to the study were cited, such as extensive exclusion criteria that could limit the findings’ generalizability. In addition, erythropoietin’s clinical uses could be limited by its potential to increase risk of hypertension and blood clots, although the authors said careful monitoring may mitigate the risk and that use of the hormone may be justified in this highly impaired population.

Based on the results, the authors characterized erythropoietin as an “interesting compound” that may have potential for enhancing the treatment of mood and memory problems in patients with treatment-resistant depression.

Information on indications, dosages, and effects of the SNRI venlafaxine extended release

Classification: Serotonin norepinephrine reuptake inhibitor (SNRI).

Common Usage: Venlafaxine is indicated for the adult treatment of major depressive disorder (MDD), generalized anxiety disorder (GAD), social anxiety disorder/social phobia, and panic disorder with or without agoraphobia.

Warnings and Precautions:

Clinical worsening and suicide risk: Antidepressants may increase suicidal thoughts or behavior in some children, adolescents, and young adults, especially during the first few months of treatment or when changing the dose. No increased risk for these events has been shown for adults over 24 years of age, and the risk is decreased for adults over 65 years of age. All patients starting treatment with antidepressants should be monitored and observed closely for new or worsening symptoms of depression, suicidal thoughts or behavior, or unusual changes in behavior.

Bipolar disorder: Before starting antidepressant treatment, patients should be screened for bipolar disorder. Venlafaxine is not approved for treating bipolar depression.

Serotonin syndrome: Potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions may occur when venlafaxine is taken with other SNRIs or selective serotonin reuptake inhibitors (SSRIs), certain headache or migraine medications (triptans) or tryptophan, and drugs that impair metabolism of serotonin, including monoamine oxidase inhibitors (MAOIs). Your doctor should be notified if you develop one or more of the following: restlessness, hallucinations (seeing, hearing, feeling, or tasting something that is not actually there), loss of coordination, very rapid heartbeat, very high fever, muscle stiffness, increased or irregular blood pressure, diarrhea, nausea, vomiting, confusion, or coma.

Hypertension (high blood pressure): Venlafaxine may raise blood pressure in some patients. Your blood pressure should be under control before starting venlafaxine and should be checked regularly during venlafaxine treatment.

Mydriasis (prolonged dilation of the pupils of the eye): This has occurred in some patients taking venlafaxine. Tell your doctor before starting venlafaxine if you have a history of glaucoma or increased eye pressure.

Hyponatremia: Low sodium levels in the blood can occur when taking SNRIs or SSRIs. Contact your doctor right away if you become severely ill and have any of the following symptoms: headache, feeling weak, confusion, problems concentrating, memory problems, or feeling unsteady. In more severe or acute cases, hallucinations, fainting, seizures, coma, respiratory arrest, or death may occur.

Seizures: Venlafaxine should be used cautiously in patients with a history of seizures and should be discontinued if seizures occur.

Cholesterol levels: Measuring serum cholesterol levels should be considered during long-term venlafaxine treatment.

Cardiac risk: Venlafaxine should be used cautiously in patients with risk factors for a disturbance of the electrical activity of the heart known as QTc prolongation, or in patients concomitantly using other drugs that prolong the QTc interval.

Special Populations:

Pregnancy and nursing: Tell your doctor if you are pregnant, planning pregnancy, breastfeeding, or planning to breastfeed, as the potential benefits of venlafaxine must be weighed against the possible risks to the unborn child or infant.

Geriatrics: Elderly patients may be at greater risk of developing hyponatremia when taking SNRIs, such as venlafaxine, or SSRIs.

Pediatrics: Venlafaxine is not approved for patients younger than 18 years.

Common Side Effects: The most commonly reported side effects in clinical trials include constipation, dizziness, dry mouth, insomnia, loss of appetite, nausea, nervousness, sexual side effects, sleepiness, sweating, and weakness.

This is not a complete list of all known or potential adverse effects. Notify your prescriber or pharmacist of any symptoms that have started since you began taking this medication, changing its dose, or adding or changing other medication or diet. Take care when performing any task (such as driving a car or operating machinery) that requires your attention until you have experience with this drug and are confident you can perform the task safely.

Interactions with Other Medications:

Contraindications: Do not take venlafaxine if you are taking an MAOI, or within at least 14 days after stopping an MAOI. Allow at least 7 days before stopping venlafaxine and starting an MAOI. MAOIs include phenelzine (Nardil), tranylcypromine (Parnate), isocarboxazid (Marplan), selegiline (Eldepryl), and the antibiotic linezolid (Zyvox).

Abnormal bleeding: Taking SNRIs, such as venlafaxine, or SSRIs may increase the risk of abnormal bleeding. Taking aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Advil), aspirin, other blood thinners, or drugs that affect blood clotting such as warfarin (Coumadin) at the same time as SNRIs or SSRIs may add to the risk. Patients taking warfarin should be carefully monitored when starting or stopping SNRIs or SSRIs.

Caution is advised when using venlafaxine with triptans such as almotriptan (Axert) or sumatriptan (Imitrex); other SNRIs; SSRIs such as fluoxetine (Prozac); lithium; St. John’s wort; methylene blue; cimetidine (Tagamet); antipsychotics such as haloperidol (Haldol) or risperidone (Risperdal); other central nervous system (CNS) drugs; metoprolol (Lopressor); or ketoconazole (Nizoral). Avoid drinking alcohol while taking venlafaxine.

This is not a complete list of all known or potential drug interactions. To help prevent problems, always make sure that your pharmacist and all prescribers know about all medications you are taking, including over-the-counter drugs; dietary herbal supplements; folk or home remedies; or unusual foods, drinks, or dietary habits.

Common Dosages: Effexor XR should be taken with food in a single dose in the morning or evening at approximately the same time each day. Capsules should be swallowed whole and not divided, crushed, chewed, or placed in water. It can also be taken by carefully opening the capsule and sprinkling the contents on a spoonful of applesauce, and then swallowed immediately without chewing, followed by drinking a glass of water to make sure all the medication is swallowed.

MDD: The recommended starting dose for most patients is 75 mg/day in a single dose. Dose increases should be in increments of up to 75 mg/day, as needed, at intervals of not less than 4 days. Some patients may benefit from a lower starting dose of 37.5 mg/day for 4 to 7 days before increasing the dose to 75 mg/day. The maximum recommended daily dose is approximately 225 mg. It is not known whether higher doses are needed for severely depressed patients, and very little is known about Effexor XR at doses higher than 225 mg/day.

GAD: The recommended starting dose for most patients is 75 mg/day in a single dose. Dose increases should be in increments of up to 75 mg/day, as needed, at intervals of not less than 4 days. Some patients may benefit from a lower starting dose of 37.5 mg/day for 4 to 7 days before increasing the dose to 75 mg/day. The maximum recommended daily dose is approximately 225 mg.

Social anxiety disorder/social phobia: The recommended dose is 75 mg/day in a single dose. There is no evidence that higher doses provide any additional benefit.

Panic disorder: The recommended starting dose is 37.5 mg/day for 7 days. Dose increases should be in increments of up to 75 mg/day at intervals of not less than 7 days, to a maximum of approximately 225 mg/day if needed.

In patients with mild to moderate hepatic (liver) impairment, the total daily dose should be reduced by 50%. In some cases, it may be necessary to reduce the dose by even more than 50%, and individualization may be desirable in some patients. In patients with renal (kidney) impairment, including patients undergoing hemodialysis, it is recommended that the daily dose be reduced by 50%.

Pregnancy: Tapering the dose may be considered during the third trimester.

Geriatrics: No dose adjustments are recommended based solely on age. When individualizing the dose, extra care should be taken when increasing the dose.

Discontinuing venlafaxine should be done gradually, whenever possible. If intolerable symptoms develop during discontinuation, then resuming the previous dose may be considered, followed by gradual discontinuation at a slower rate.

37.5 mg: gray cap/peach body with “W” and “Effexor XR” on the cap and “37.5” on the body.

75 mg: peach cap and body with “W” and “Effexor XR” on the cap and “75” on the body.

150 mg: dark orange cap and body with “W” and “Effexor XR” on the cap and “150” on the body.

Storage: Store this medication at controlled room temperature (59°F to 86°F) in a tightly closed, child-, light-, and moisture-resistant container. If you have difficulty opening child-resistant containers, your pharmacist can provide you with a container that is easier to open. Keep the medication out of direct sunlight and avoid storing it in a warm and humid area, such as the bathroom or kitchen, to avoid deterioration. To prevent accidental poisoning, keep all medications out of the reach of children or adults with dementia. Do not take expired medication. Do not transfer medication from one container to another. Carefully discard discontinued medication where children, pets, or adults with dementia cannot find it.

Information on indications, dosages, and potential adverse effects of the anticonvulsant oxcarbazepine

Classification: Anticonvulsant.

Common usage: Oxcarbazepine is indicated for use as monotherapy or adjunctive therapy in the treatment of partial seizures (a subtype of epilepsy) in adults and as monotherapy in the treatment of partial seizures in children ages 4 years and older with epilepsy, and as adjunctive therapy in children ages 2 years and older with epilepsy.

Warnings: Suicidal behavior and ideation: Antiepileptic drugs (AEDs), including oxcarbazepine, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Anaphylaxis and angioedema: Anaphylaxis (severe allergic reaction) and angioedema (swelling) involving the throat, lips, and eyelids have been reported in patients taking oxcarbazepine. If any such reaction occurs, you should discontinue use of oxcarbazepine.

Serious dermatological reactions: Serious skin reactions, such as Stevens-Johnson syndrome, have been reported in association with oxcarbazepine.

Patients with a past history of hypersensitivity reaction to carbamazepine: Of patients who have had hypersensitivity to carbamazepine, 25 to 30% will experience a reaction to oxcarbazepine. Caution should be used in prescribing oxcarbazepine for these patients.

Important side effects: During research studies, oxcarbazepine has been reported to cause problems with balance, shaking, clumsiness, unsteadiness, or dizziness. Potential vision problems include double vision, blurry vision, or uncontrolled side-to-side or rotating movements of the eye that are usually not noticed by the patient as much as someone looking at the patient. Other adverse effects include changes in mood, agitation, confusion, disorientation, memory problems, or loss of consciousness. Cough, sore throat, shortness of breath, wheezing, difficulty breathing, or sinus infection also may occur. Other possible effects include easy bruising; fever; decreased urination or increased thirst; fast or irregular heartbeat; muscle cramps; and low blood pressure, including faintness or lightheadedness when getting up from a lying or sitting position.

This is not a complete list of all known or potential adverse effects. Notify your prescriber of any symptoms that have started since you began taking this medication, changing its dose, or adding or changing other medication or diet. Take care when performing any task (such as driving a car or operating machinery) that requires your attention until you have experience with this drug and are confident you can perform the task safely.

Interactions with other medications: Drugs that can reduce the effect of oxcarbazepine include other anticonvulsants such as carbamazepine (Tegretol), phenobarbital (Luminal), phenytoin (Dilantin), and valproate (Depakene, Depakote). Oxcarbazepine can reduce the effectiveness of oral contraceptives and some cardiac medications, such as felodipine (Plendil) or verapamil (Calan).

This is not a complete list of all known or potential drug interactions. To help prevent problems, always make sure that your pharmacist and all prescribers know about all medications you are taking, including over-the-counter drugs; dietary herbal supplements; folk or home remedies; or unusual foods, drinks, or dietary habits.

Common dosages: The usual initial adult dose when oxcarbazepine is used as monotherapy is 300 mg twice daily, which may be increased by 300 mg daily at three-day intervals to a maximum daily dose of 1,200 mg. The dose may be increased by a maximum of 600 mg daily at weekly intervals if adding to or converting from another anticonvulsant. Some patients may benefit from higher doses up to 2,400 mg daily, but adverse effects increase at higher doses as well.

If a dose is missed, it should be taken as soon as possible unless it is almost time for the next dose; in that case, skip the missed dose and resume your routine schedule. Do not take a double dose.

In pediatric patients ages 4 to 16 years, treatment should be initiated at a daily dose of 8 to 10 mg/kg generally not to exceed 600 mg/day, given in a twice-daily regimen.

Identification: The 150-mg tablets of oxcarbazepine are yellow, film-coated, ovaloid, slightly biconvex, and scored on both sides, and are imprinted with “T/D” on one side and “C/G” on the other. The 300-mg tablets are yellow, film-coated, ovaloid, slightly biconvex, and scored on both sides. They are imprinted with “TE/TE” on one side and “CG/CG” on the other. The 600-mg tablets are yellow, film-coated, ovaloid, slightly biconvex, and scored on both sides. They are imprinted with “TF/TF” on one side and “CG/CG” on the other. Oxcarbazepine is also available as a 300 mg/5 mL (60 mg/mL) oral suspension that is off-white to slightly brown or slightly red in color.

Storage: Store this medication at normal room temperature (59°F to 86°F), in a tightly closed, child-, light-, and moisture-resistant container. If you have difficulty opening child-resistant containers, your pharmacist can provide you with a container that is easier to open. Keep the medication out of direct sunlight and avoid storing it in a warm and humid area, such as the bathroom or kitchen, to avoid deterioration. To prevent accidental poisoning, keep all medications out of the reach of children or adults with dementia. Do not take expired medication. Do not transfer medication from one container to another. Carefully discard discontinued medication where children or adults with dementia cannot find it.

Common usage: Sertraline is indicated for the treatment of depression, panic disorder, post-traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), social anxiety disorder, and obsessive-compulsive disorder (OCD) in adults. It is also indicated for the treatment of OCD in children and adolescents ages 6 to 17. Sertraline is not approved for treating depression in children.

Important side effects: Most side effects experienced by patients taking sertraline are mild in severity and do not usually result in the need to stop this medication. The most common side effects experienced by patients taking sertraline include sedation, trouble sleeping, decreased appetite, dry mouth, diarrhea/loose stools, stomach upset, increased sweating, tremor, and agitation. Children taking sertraline may also experience other side effects, such as excessive movement or twitching, not “feeling well,” weight loss, manic or excited behavior, or rapid mood swings.

Clinical worsening and suicide risk:

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. There has been a longstanding concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients. Antidepressants increased the risk of suicidality in short-term studies in children and adolescents with MDD and other psychiatric disorders.

As with other SSRIs, sertraline has been associated with cases of clinically significant hyponatremia (a low sodium level in the blood) in elderly patients.

This is not a complete list of all known or potential adverse effects. Notify your prescriber of any symptoms that have started since you began taking this medication, changing its dose, or adding or changing other medication or diet. Take care when performing any task (such as driving a car or operating machinery) that requires your attention until you have experience with this drug and are confident you can perform the task safely.

Interactions with other medications:Sertraline should not be used with monoamine oxidase inhibitors (MAOIs) such as phenelzine (Nardil), selegiline (Eldepryl), and tranylcypromine (Parnate). If any of these medications were used and discontinued, a waiting period of 14 days should elapse before beginning treatment with sertraline. When on an SSRI, consideration should be given prior to the addition of another medication (prescription or over-the-counter) that increases serotonin, because of concerns about serotonin syndrome.

This is not a complete list of all known or potential drug interactions. To help prevent problems, always make sure that your pharmacist and all prescribers know about all medications you are taking, including over-the-counter drugs, dietary herbal supplements, folk or home remedies, or unusual foods, drinks, or dietary habits.

Common dosages: For depression, PMDD, and OCD in adults, sertraline should be administered at a dose of 50 mg/day. For panic disorder, PTSD, and social anxiety disorder in adults, sertraline should be started at 25 mg/day, and increased to 50 mg/day after one week. For treatment of OCD in children ages 6 to 12, the initial dose is usually 25 mg/day; for children ages 13 to 17, the recommended dose is 50 mg/day. Dosages can be increased gradually, if necessary, up to 200 mg/day.

Identification: Sertraline is available in 25-mg, 50-mg, and 100-mg capsular-shaped scored tablets. The 25-mg tablet is light green, engraved on one side with “ZOLOFT” and on the other side scored and engraved with “25 mg”. The 50-mg tablet is light blue, engraved on one side with “ZOLOFT” and on the other side scored and engraved with “50 mg”. The 100-mg tablet is light yellow, engraved on one side with “ZOLOFT” and on the other side scored and engraved with “100 mg”.

Sertraline is also available in a clear, colorless oral concentrate (20 mg/mL). The oral concentrate must be diluted before use. Just before taking, use the dropper provided to remove the required amount of oral concentrate and mix with 4 ounces (half a cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice only. Do not mix the oral concentrate with anything other than the liquids listed. The dose should be taken immediately after mixing. At times, a slight haze may appear after mixing; this is normal.To make sure you take the entire dose, add a little more water to the same glass, swirl gently, and drink right away. Do not take the liquid form of sertraline if you are taking disulfiram (Antabuse), as the concentrate may contain alcohol.

Storage: Sertraline should be stored at controlled room temperature (59° F to 86° F), in a tightly closed, child-, light-, and moisture-resistant container. If you have difficulty opening child-resistant containers, your pharmacist can provide you with a container that is easier to open. Keep the medication out of direct sunlight and avoid storing it in a warm and humid area, such as the bathroom or kitchen, to avoid deterioration. To prevent accidental poisoning, keep all medications out of the reach of children or adults with dementia. Do not take expired medication. Do not transfer medication from one container to another. Carefully discard discontinued medication where children or adults with dementia cannot find it.

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Lawrence H. Price, M.D., is a professor in the department of Psychiatry and Human Behavior at the Brown Medical School. He is also the director of research and the
clinical director of Butler Hospital in Providence, RI. Dr. Price
conducts research on a range of mood disorders and pharmacological
therapies and supervises the work of psychiatry residents and fellows.